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Non-alcoholic steatohepatitis (NASH) is a highly prevalent, chronic liver disease characterized by hepatic lipid accumulation, inflammation, and concomitant fibrosis. Up to date, no anti-NASH drugs have been approved. In this study, we reproduced key NASH characteristics in vitro by exposing primary human hepatocytes (PHH), human skin stem cell-derived hepatic cells (hSKP-HPC), HepaRG and HepG2 cell lines, as well as LX-2 cells to multiple factors that play a role in the onset of NASH. The obtained in vitro disease models showed intracellular lipid accumulation, secretion of inflammatory chemokines, induced ATP content, apoptosis, and increased pro-fibrotic gene expression. These cell systems were then used to evaluate the anti-NASH properties of eight peroxisome proliferator-activated receptor (PPAR) agonists (bezafibrate, elafibranor, fenofibrate, lanifibranor, pemafibrate, pioglitazone, rosiglitazone, and saroglitazar). PPAR agonists differently attenuated lipid accumulation, inflammatory chemokine secretion, and pro-fibrotic gene expression.Based on the obtained readouts, a scoring system was developed to grade the anti-NASH potencies. The in vitro scoring system, based on a battery of the most performant models, namely PHH, hSKP-HPC, and LX-2 cultures, showed that elafibranor, followed by saroglitazar and pioglitazone, induced the strongest anti-NASH effects. These data corroborate available clinical data and show the relevance of these in vitro models for the preclinical investigation of anti-NASH compounds.

Original languageEnglish
Pages (from-to)293-311
Number of pages19
JournalCell Biology and Toxicology
Issue number2
Early online date1 Jul 2020
Publication statusPublished - Apr 2021

Bibliographical note

Funding Information:
This work was funded by grants of Research Foundation Flanders (1S10518N, 12H2216N, 1S73019N, and G042019N), Onderzoeksraad Vrije Universiteit Brussel, and the Research Chair Mireille Aerens for Alternatives to Animal Testing.

Publisher Copyright:
© 2020, Springer Nature B.V.

Copyright 2021 Elsevier B.V., All rights reserved.


  • Elafibranor
  • In vitro
  • Non-alcoholic steatohepatitis (NASH)
  • Peroxisome proliferator-activated receptor (PPAR)
  • Pioglitazone
  • Saroglitazar


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